U.S. patent number 9,487,496 [Application Number 14/441,726] was granted by the patent office on 2016-11-08 for process for the preparation of cabazitaxel and its intermediates.
This patent grant is currently assigned to Intas Pharmaceuticals Limited. The grantee listed for this patent is INTAS PHARMACEUTICALS LIMITED. Invention is credited to Mettilda Lourdusamy, Raghvendra Jayantibhai Patel, Ioan Iosif Radu, Rahul Chandrashayi Saxena, Sandeep Bachubhai Shah.
United States Patent |
9,487,496 |
Lourdusamy , et al. |
November 8, 2016 |
Process for the preparation of cabazitaxel and its
intermediates
Abstract
The present invention relates to a novel process for preparation
of cabazitaxel (I) starting from 10-Deacetyl baccatin or derivative
that involves methylation of 7, 10 --OH groups. Also provided is a
novel process using chiral bis-lactam linker for the synthesis of
cabazitaxel.
Inventors: |
Lourdusamy; Mettilda (Quebec,
CA), Radu; Ioan Iosif (Quebec, CA), Saxena;
Rahul Chandrashayi (Ahmedabad, IN), Patel; Raghvendra
Jayantibhai (Ahmedabad, IN), Shah; Sandeep
Bachubhai (Ahmedabad, IN) |
Applicant: |
Name |
City |
State |
Country |
Type |
INTAS PHARMACEUTICALS LIMITED |
Ahmedabad |
N/A |
IN |
|
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Assignee: |
Intas Pharmaceuticals Limited
(Ahmedabad, IN)
|
Family
ID: |
49917689 |
Appl.
No.: |
14/441,726 |
Filed: |
October 31, 2013 |
PCT
Filed: |
October 31, 2013 |
PCT No.: |
PCT/IN2013/000669 |
371(c)(1),(2),(4) Date: |
May 08, 2015 |
PCT
Pub. No.: |
WO2014/072996 |
PCT
Pub. Date: |
May 15, 2014 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20150307468 A1 |
Oct 29, 2015 |
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Foreign Application Priority Data
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|
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Nov 9, 2012 [IN] |
|
|
3256/MUM/2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D
305/14 (20130101) |
Current International
Class: |
C07D
305/00 (20060101); C07D 305/14 (20060101) |
Field of
Search: |
;549/510 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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102060815 |
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May 2011 |
|
CN |
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102285947 |
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Dec 2011 |
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CN |
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102417491 |
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Apr 2012 |
|
CN |
|
Other References
Evans, et al., "Mild Alcohol Methylation Procedures for the
Synthesis of Polyoxygenated Natural Products. Applications to the
Synthesis of Lonomycin A", Tetrahedron Letters, vol. 35, No. 39,
pp. 7171-7172, Jan. 1, 1994. cited by applicant .
International Search Report issued in PCT International Application
No. PCT/IN2013/000669, mailed Jul. 22, 2014. cited by
applicant.
|
Primary Examiner: Oh; T. Victor
Attorney, Agent or Firm: Hamre, Schumann, Mueller &
Larson, P.C.
Claims
We claim:
1. A process to prepare cabazitaxel (I) comprising: methylating a
compound of formula II ##STR00029## in which X represents H or a
side chain of formula (III) ##STR00030## Z represents a hydroxy
protecting group, R.sub.1 is --C(O)OC(CH.sub.3).sub.3, with methyl
trifluoromethanesulfonate in the presence of a solvent to get a
compound of formula (IV) ##STR00031##
2. A process to prepare cabazitaxel comprising: methylating a
compound of formula II ##STR00032## wherein X represents a side
chain of formula (III), Z=triethyl silyl, R.sub.1 is
--C(O)OC(CH.sub.3).sub.3 ##STR00033## with methyl
trifluoromethanesulfonate in the presence of a solvent to get a
compound of formula (XII) ##STR00034##
3. A process to prepare cabazitaxel comprising: selective 2'
deprotection of a compound of formula (XIII) in the presence of a
solvent ##STR00035##
4. A process to prepare cabazitaxel comprising: reacting a compound
of formula (V) ##STR00036## wherein R.sub.1 is
--C(O)OC(CH.sub.2).sub.3, Ar is a phenyl group and L is a cleavable
linker with a compound of formula (VI) in the presence of a solvent
##STR00037## to get a compound of formula (VII) ##STR00038##
wherein L is selected from a compound having the following
structural formula ##STR00039## wherein Rc and R'c are identical or
different and are alkyl, aryl or hydrogen, Rd and R'd are identical
or different and are alkyl, aryl or hydrogen, Rf and R'f are
identical or different and are alkyl, aryl or hydrogen, Rg and R'g
are identical or different and are alkyl, aryl or hydrogen, and W
is an alkyl having 1 to 30 carbon atoms.
5. A process to prepare cabazitaxel comprising: a. methylating a
compound of formula (VIII) with methyl trifluoromethanesulfonate
##STR00040## to get a compound of formula (VI); ##STR00041## b.
reacting a compound of formula (VI) with a compound of formula
(IX); ##STR00042## to get a compound of formula (X); ##STR00043##
wherein W=alkyl having C.sub.1-C.sub.30, c. treating a compound of
formula (X) in the presence of a solvent and a base to obtain
cabazitaxel (I).
6. A process according to claim 1, wherein the solvent is selected
from the group consisting of a nitrile, a chlorinated hydrocarbon,
a polar aprotic solvent, an ester, an ether, a cyclic ether and
mixtures thereof.
7. A process according to claim 1, wherein the methylation is
carried in the presence of a base.
8. A process according to claim 7, wherein the base is selected
from lithium hexamethyl disilazide, sodium hexamethyldisilazide and
potassium hexamethyl disilazide.
9. A process according to claim 2, wherein the solvent is selected
from the group consisting of a nitrile, a chlorinated hydrocarbon,
a polar aprotic solvent, an ester, an ether, a cyclic ether and
mixtures thereof.
10. A process according to claim 2, wherein the methylation is
carried in the presence of a base.
11. A process according to claim 10, wherein the base is selected
from lithium hexamethyl disilazide, sodium hexamethyldisilazide and
potassium hexamethyl disilazide.
12. A process according to claim 3, wherein the solvent is selected
from the group consisting of a nitrile, a chlorinated hydrocarbon,
a polar aprotic solvent, an ester, an ether, a cyclic ether and
mixtures thereof.
13. A process according to claim 3, wherein the deprotection is
carried in the presence of a base.
14. A process according to claim 13, wherein the base is selected
from lithium hexamethyl disilazide, sodium hexamethyldisilazide and
potassium hexamethyl disilazide.
15. A process according to claim 4, wherein the solvent is selected
from the group consisting of a nitrile, a chlorinated hydrocarbon,
a polar aprotic solvent, an ester, an ether, a cyclic ether and
mixtures thereof.
16. A process according to claim 4, wherein the reaction is carried
in the presence of a base.
17. A process according to claim 16, wherein the base is selected
from lithium hexamethyl disilazide, sodium hexamethyldisilazide and
potassium hexamethyl disilazide.
18. A process according to claim 5, wherein solvent is selected
from the group consisting of a nitrile, a chlorinated hydrocarbon,
a polar aprotic solvent, an ester, an ether, a cyclic ether and
mixtures thereof.
19. A process according to claim 5, wherein the methylation is
carried in the presence of a base.
20. A process according to claim 19, wherein the base is selected
from lithium hexamethyl disilazide, sodium hexamethyldisilazide and
potassium hexamethyl disilazide.
Description
FIELD OF THE INVENTION
The present invention relates to a novel process for the
preparation of Cabazitaxel and its intermediates.
BACKGROUND OF THE INVENTION
Cabazitaxel exhibits notable anticancer and antileukaemic
properties. Cabazitaxel, chemically known as
4-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1-hydroxy-7.beta.
10.beta.-dimethoxy-9-oxo-tax-11-en-13.alpha.-yl(2R,3S)-3-tert-butoxycarbo-
nylamino-2-hydroxy-3-phenylpropionate and is represented by the
following structural formula:
##STR00001##
The compound was disclosed in U.S. Pat. No. 5,847,170 (hereinafter
referred as US' 170). It is sold under brand name Jevtana as its
acetone solvate. Cabazitaxel is prepared according to the method
which is described more particularly in US' 170.
Although Cabazitaxel is a very important second line treatment for
the metastatic CRPC, there are still limited reports on the
synthesis of Cabazitaxel. Aventis reported the first synthetic
route of Cabazitaxel in US' 170 starting from 10-deacetylbaccatin
III (10-DAB). The synthesis consisted of more than five steps with
a very low reported yield.
U.S. Pat. No. 5,962,705 disclosed a process for the taxoid
derivatives using alkylating agents such as alkyl halide, alkyl
sulfate, oxonium in the presence of an anionization agent.
CN 102060815 provided a method for the conversion of Docetaxel to
Cabazitaxel by using dimethylsulfate as an alkylating agent in a
weakly alkaline organic solvent (pyridine).
CN 102285947 reported the synthesis of Cabazitaxel by methylating
the 7 and 10-OH in 10-DAB simultaneously to furnish
7,10-dimethyl-10-DAB, which was then coupled with a protected
(3R,4S)-.beta.-lactam followed by deprotection of the 2'-OH, the
total yield is approximately 18.0% for 3 steps.
Thus, there is a need for developing a process for preparation of
cabazitaxel and its key intermediates which is not only feasible at
industrial scale but also meets economics of scale in terms of
yield.
OBJECTS OF THE INVENTION
It is an object of the present invention is to provide a novel
process for the preparation of Cabazitaxel and its key
intermediate.
Another object of the present invention is to provide a process for
preparing Cabazitaxel using chiral auxiliaries.
Another object of the present invention is to provide a process for
preparing Cabazitaxel from Docetaxel.
SUMMARY OF THE INVENTION
In one aspect the present invention provides a process for
preparation of cabazitaxel (I) comprising methylation of compound
of formula (II)
##STR00002## in which X represents H or side chain of formula
(III)
##STR00003##
Z represents a hydroxy protecting group, R1 is
C(O)OC(CH.sub.3).sub.3,
Using a methylating agent, methyl trifluoromethansulfonate to get
compound of formula (IV)
##STR00004## converting, compound of formula (IV) to cabazitaxel
(I).
Yet another aspect of the present invention provides process to
prepare cabazitaxel (I) comprising
reacting a compound of formula (II) wherein Z=triethyl silyl
with methyl trifluoromethansulfonate to obtain compound of formula
(XII)
##STR00005## converting compound of formula (XII) to
cabazitaxel
In another aspect the present invention provides a process to
prepare cabazitaxel (I) comprising selective 2' deprotection of
compound of formula (XIII)
##STR00006##
In accordance with another aspect of the present invention there is
provided a process for preparation of cabazitaxel where novel and
chiral bis lactam of formula (V)
##STR00007##
R1 is defined above, Ar is a phenyl group and L is a cleavable
linker
is reacted with a suitable taxane precursor of formula (VI)
##STR00008## to give a compound of formula (VII)
##STR00009## cleaving the linker from compound of formula (VII) to
get cabazitaxel (I).
In a further aspect the present invention provides a process to
prepare cabazitaxel which comprises reacting compound of formula
(VIII)
##STR00010## with methyl trifluorornethansulfonate to obtain
compound of formula (VI)
##STR00011## reacting compound of formula (VI) with compound of
formula (IX)
##STR00012##
BOC.dbd.CO(O)C(C+H3).sub.3, W=alkyl of 1-30 carbon atom
to get compound of formula (X)
##STR00013## converting compound of formula (X) to cabazitaxel
(I)
DETAILED DESCRIPTION
The present invention provides process for preparing
cabazitaxel.
Accordingly, the present invention provides a process for
methylation of the two hydroxyl groups at 7 and 10 position of
10-deacetylbaccatin or derivatives thereof of formula (II)
##STR00014##
In which, X represents H or side chain of formula (III)
##STR00015## wherein Z represents hydroxy protecting group and R1
is C(O)OC(CH3).sub.3, using methyl trifuoromethanesulfonate as
methylating agent. This process includes direct conversion of
docetaxel to cabazitaxel or methylation of 10-deacetyl baccatin and
further conversion of 7,10 dimethyl baccatin to cabazitaxel.
More specifically, according to one of the aspects of the present
invention, processes for preparation of cabazitaxel using docetaxel
are described.
Accordingly, in an embodiment the present invention provides a
process to prepare cabazitaxel wherein compound of structural
formula (XI)
##STR00016## is reacted with methyl trifluoromethansulfonate to get
compound of formula (XII)
##STR00017##
The compound of formula (XII) can be converted to cabazitaxel
The process can be further exemplified as following scheme
##STR00018##
In another aspect the present invention provides a process for
preparing cabazitaxel by selective deprotection of compound of
formula (XIII)
##STR00019##
The process can be further exemplified as following-scheme
##STR00020##
In the process of present invention protecting group can be
selected from any suitable hydroxy protecting group preferably a
silyl protecting group such as triethyl silyl is used for the
purpose of present invention.
The protection reaction or can be carried out in presence of a
suitable solvent and base. Solvent can be selected from any
suitable solvent such from the group comprising of nitrile,
chlorinated hydrocarbon, polar aprotic solvent, ethers and mixture
thereof. Base can be selected from inorganic such as alkali metal
or alkali earth-metal carbonate or bicarbonates, metal hydroxide,
organic base can be selected from group consisting of alkyl amine
like triethyl amine, morpholine, pyridine like dimethyl amino
pyridine, piperidine or like.
Protection of 2'-OH is followed by methylation of 7 and 10 hydroxyl
group. The methylation is carried out by using methyl
trifluoromethansulfonate (methyl triflate). The reaction can be
carried out in presence of solvent and base. The solvent used in
methylation reaction can be selected from any suitable organic
solvent such as solvent selected from the class of ester, ketone,
ether, cyclic ether or like. The base can be selected from any base
suitably used in methylation preferably salts hexamethyldisilazide
are used in present process. 2',7,10 methylation can also be
carried out in presence of suitable solvent and base.
The protected cabazitaxel thus prepared can be subjected to
deprotection or selective deprotection in presence of base.
Preferably a mild base such as tetrabutyl ammonium fluoride is
used.
The above process of protection of --OH group, methylation and
deprotection or 2',7,10 methylation and 2' selective deprotection
to get cabazitaxel can be carried out in a single step i.e. without
isolating the intermediate stages or in multiple steps.
Another aspect of the present invention is to provide a process for
the preparation of Cabazitaxel, where novel, chiral bis-lactams of
formula (V)
##STR00021##
R1 is defined above, Ar is a phenyl group and L is a cleavable
linker is reacted with a suitable taxane precursor having a free
C-13 hydroxy group.
Accordingly, cabazitaxel can be prepared by reacting taxane
precursor of formula (VI):
##STR00022## with a compound of formula (V) to give a compound of
formula (VII)
##STR00023##
Cabazitaxel is released from the compound of formula (VII) by
cleaving the linker.
The cleavable linker L can be chiral or non-chiral, preferably
selected from the group consisting of hydrolysable ketals, acetals,
silyl, esters, diesters and hydrogenolysable benzyl group.
Further L can be selected form compound of structural formula
##STR00024## wherein Rc and R'c, identical or different are alkyl,
aryl or hydrogen, Rd and R'd, identical or different are alkyl,
aryl or hydrogen, Rf and R'f, identical or different are alkyl,
aryl or hydrogen, Rg and R'g, identical or different are alkyl,
aryl or hydrogen; W is an alkyl. Further W can be an alkyl of 1-30
carbon atoms.
In an embodiment the taxane precursor can be prepared by reacting
10-deacetyl baccatin III of formula (VIII)
##STR00025## with methylating agent, preferably methyl
trifluoromethansulfonate. The methylation reaction is carried out
in presence of a base preferably the base used herein is salt of
hexamethyl disilazide like sodium, potassium, lithium hexamethyl
disilazide. The 7,10-dimethoxy-10-deacetyl baccatin-III (VI) thus
prepared
##STR00026## is reacted with N-boc-bis lactam of formula (IX)
##STR00027##
BOC.dbd.CO(O)C--(CH3), W=alkyl of 1-30 carbon atoms to give
compound of formula (X)
##STR00028##
The reaction, is carried out in presence of a suitable solvent and
base. The process comprises reacting in presence of solvent
selected from class of ether, cyclic ether, ester, halogenated
solvent, hydrocarbon, protic or aprotic solvent. The base can be
selected from any suitable base for such reaction preferably the
present invention uses salt of hexa methyl disilazide such as
sodium potassium or lithium hexamethyl disilazide.
Compound of formula (X) is subjected to a reaction for cleavage of
linker to get cabazitaxel. The reaction can be carried out in
presence of solvent and base. Solvent can be selected from any
suitable solvent like ether such as tetrahydrofuran, ketone such as
acetone, ester such as ethyl acetate, alkane such as heptane,
alcohol such as isopropyl alcohol, nitrile such acetonitrile or
like. The solvent can be used as single solvent, as mixture or as a
solvent antisolvent combination thereof.
Cabazitaxel thus obtained can be further purified by treating with
solvents, such as acetonitrile, diethyl ether, benzyloxy methyl
ether, benzyl ether, petroleum ether, ester such as ethyl acetate,
alcohol such as ethanol, methanol, isopropanol either as a single
solvent or a mixture of solvents in different ratios, preferably in
acetonitrile and an alcohol preferably methanol. Cabazitaxel could
also be purified by column chromatography but yields may be at
lower side.
Following are the specific examples describing the invention. These
examples are not intended to limit the scope of the invention in
any way.
EXAMPLES
Example 1
Preparation of (2'-Tes-docetaxel) (XI)
To a mixture of docetaxel (807 mg) in 25 ml of dichloromethane at
0.degree. C. was added dimethylaminopyridine, (122 mg) and
triethylamine (0.278 ml) followed by triethyl silyl chloride (150
mg). The product was isolated by extraction followed by evaporation
of solvent, purified over silica gel using hexane/acetone as eluent
to obtain approximately 800 mg of 2'-Tes-docetaxel, in
approximately 90% yield.
Example 2
Preparation of 2'-Tes-7,10 dimethoxy-docetaxel (XII)
To 2'-Tes-docetaxel (500 mg) in 10 ml of THF at -30 to -50.degree.
C. was added LiHMDS, (1 ml) and methyl trifluoromethansulfonate
(0.120 ml). The product was isolated by extraction followed by
evaporation of solvent, purified over silica gel using
dichloromethane/methanol as eluent to obtain approximately 464 mg
of 2'-Tes-7,10-dimethoxy-docetaxel, in approximately 90% yield
Example 3
Preparation of Cabazitaxel (I)
To 2'-Tes-7,10-dimethoxy-Tes-docetaxel (380 mg) in 10 ml of
tetrahydrofuran at room temperature was added
tetrabutylammoniumfluoride, (800 ul). The product is isolated by
extraction and evaporation of solvent, purified over silica gel
using dichloromethane/methanol as eluent to obtain approximately
275 mg of Cabazitaxel, in approximately 80% yield.
Example 4
Preparation of 2',7, 10-trimethoxy-docetaxel (XIII)
To Docetaxel (2 g) in 25 ml of tetrahydrofuran at -30 to
-50.degree. C. was added LiHMDS, (7.4 ml) and methyl
trifluoromethansulfonate (0.815 ml). Followed by extraction and
evaporation of solvent, purified over silica gel using
dichloromethane/methanol as eluent to obtain approx 1.7 g of 2'7,
10-trimethoxy-docetaxel, in approximately 80% yield
Example 5
Preparation of Cabazitaxel (I)
To trimethoxy-Docetaxel (850 mg) in 25 ml of dichloromethane at
0.degree. C. was added aqueous solution of HBr (2 ml) and allowed
the reaction to complete, product was isolated by extraction and
evaporation of solvent, purified over silica gel using
dichloromethane/methanol as eluent to obtain approximately 600 mg
of cabazitaxel, in approximately 72% yield
Example 6
Preparation of 7,10-dimethoxy-10-deacetyl baccatin III (VI)
Under Argon, 2.43 g of deacetyl baccatin in 50 ml of
tetrahydrofuran was cooled to -30 to -50 C followed by the addition
of 1.23 ml of Methyl triflate and 9.8 ml of 1M LiHMDS. Product was
isolated by extraction followed by evaporation of solvent, purified
over silica gel using dichloromethane/methanol as eluent to obtain
approximately 2.2 g of 7,10-dimethoxy-deacetyl baccatin, in
approximately 87% yield
Example 7
Preparation of compound of formula (X)
To 8.2 g, of 7,10-dimethoxy-deacetyl baccatin in a mixture of
tetrahydrofuran and dimethylformamide was added 7.363 g
N-Boc-bis-lactam and 15 ml of 1 M LiHMDS at -20.degree. C. to -30 C
under argon product was isolated by extraction, followed by
evaporation of the solvent to afford approximately 17 g of dimer
compound of formula (XI).
Example 8
Preparation of Cabazitaxel (I)
To 3 g of the dimer (XI), in 20 ml of tetrahydrofuran, at 0.degree.
C. was added 3.8 nil of tetrabutyl ammonium fluoride and left
stirring under argon. Product was isolated by extraction followed
by evaporation of the solvent to afford approximately 3.17 g of
Cabazitaxel.
* * * * *